Spatiotemporal Modeling of Mitochondrial Network Architecture

Abstract

In many cell types, mitochondria undergo extensive fusion and fission to form dynamic, responsive network structures that contribute to a number of homeostatic, metabolic, and signaling functions. The relationship between the dynamic interactions of individual mitochondrial units and the cell-scale network architecture remains an open area of study. In this work, we use coarse-grained simulations and approximate analytic models to establish how the network morphology is governed by local mechanical and kinetic parameters. The transition between fragmented structures and extensive networks is controlled by local fusion-to-fission ratios, network density, and geometric constraints. Similar fusion rate constants are found to account for the very different structures formed by mammalian networks (poised at the percolation transition) and well-connected budding yeast networks. Over a broad parameter range, the simulated network structures can be described by effective mean-field association constants that exhibit a non-linear dependence on the microscopic non-equilibrium fusion, fission, and transport rates. Intermediate fusion rates are shown to result in the highest rates of network remodeling, with mammalian mitochondrial networks situated in a regime of high turnover. Our modeling framework helps to elucidate how local parameters that govern mitochondrial interactions give rise to spatially resolved dynamic network structures at the cellular scale.